This proposal explores the use of a tissue-specific antigen, the thyroid peroxidase enzyme (TPO), is a thyroid-specific membrane antigen that is expressed on most follicular cancers and a substantial proportion of papillary cancers. The impetus for selecting TPO as a target antigen for the cellular immunotherapy of thyroid cancer comes from its role as the major human autoantigen in autoimmune thyroiditis. In this disorder, an intense lymphocytic thyroiditis is associated with cytotoxic cellular immunity to thyroid cells and eventually results in the destruction of the thyroid. The importance of this observation is two fold; TPO is a protein that has been identified as being immunogenic in man, and immune responses to TPO can mediate the destruction of antigen-bearing cells. It is proposed to evaluate the hypothesis that thyroid peroxidase (TPO)- specific immunity is present in thyroid cancer patients and differs from that seen in patients with autoimmune thyroid disease. Further, we hope to identify aspects of TPO specific immunity in thyroid cancer patients might be augmented or altered as a strategy for the immunotherapy of thyroid cancer. It is proposed to evaluate this hypothesis in relation to the following specific aims: 1. Characterize TPO expression and structure on thyroid cancers. 2. Identify and characterize TPO-specific serologic immune responses in patients with thyroid cancer and compare it to that seen in patients with Hashimoto's thyroiditis. 3. Identify and characterize TPO-specific cellular immune responses in patients with thyroid cancer and Hashimoto's thyroiditis. The anti-TPO immune response in both the thyroid and peripheral blood of cancer patients will then be compared and contrasted to the cytotoxic immune responses seen in patients with autoimmune thyroiditis to identify specific differences. It is hoped that differences could be identified that would suggest manipulations of the immune response to TPO in patients with thyroid cancer that could mediate tumor cytotoxicity. This project is being proposed as a Fogarty International Research Collaborative Agreement because of a unique situation. Dr. Endre Nagy is located at the University of Debrecen in Hungary; a center for the evaluation of thyroid disease and cancer. Dr. Nagy has recently finished a fellowship in the United States and he is experienced in all of the immune studies required for the completion of this study. The Principal Investigator, Dr. Baker, has worked with Dr. Nagy on studies involving autoimmune thyroid disease during his fellowship at Walter Reed, and can attest to his tremendous facility with these techniques. TPO constructs are being produced in the Principal Investigator's laboratory as a part of his parent grant and he has already developed most of the immunologic assays needed for the performance of this grant.